دورية أكاديمية
HGG-60. Structural variants shape driver combinations and outcomes in pediatric high-grade glioma
| العنوان: | HGG-60. Structural variants shape driver combinations and outcomes in pediatric high-grade glioma |
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| المؤلفون: | Dubois, Frank, Shapira, Ofer, Greenwald, Noah, Zack, Travis, Wala, Jeremiah, Tsai, Jessica, Crane, Alexander, Baguette, Audrey, Hadjadj, Djihad, Harutyunyan, Ashot, Kumar, Kiran, Blattner-Johnson, Mirjam, Vogelzang, Jayne, Sousa, Cecilia, Kang, Kyung Shin, Sinai, Claire, Wang, Dayle, Khadka, Prasidda, Malkin, Hayley, Ho, Patricia, O'Rourke, Ryan, Zhang, Shu, Gold, Rose, Deng, Davy, Serrano, Jonathan, Snuderl, Matija, Jones, Chris, Wright, Karen, Chi, Susan, Grill, Jacques, Kleinman, Claudia, Goumnerova, Liliana, Jabado, Nada, Jones, David, Kieran, Mark, Ligon, Keith, Beroukhim, Rameen, Bandopadhayay, Pratiti |
| المصدر: | Neuro-Oncology ; volume 24, issue Supplement_1, page i75-i76 ; ISSN 1522-8517 1523-5866 |
| بيانات النشر: | Oxford University Press (OUP) |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Cancer Research, Neurology (clinical), Oncology |
| الوصف: | Pediatric high-grade gliomas (pHGGs), encompassing hemispheric and diffuse midline gliomas (DMGs), remain a devastating disease. The last decade has revealed oncogenic drivers including single nucleotide variants (SNVs) in histones. However, the contribution of structural variants (SVs) to gliomagenesis has not been systematically explored due to limitations in early SV analysis approaches. Using SV algorithms, we recently created, we analyzed SVs in whole-genome sequences of 179 pHGGs including a novel cohort of treatment naïve samples–the largest WGS cohort assembled in adult or pediatric glioma. The most recurrent SVs targeted MYC isoforms and receptor tyrosine kinases, including a novel SV amplifying a MYC enhancer in the lncRNA CCDC26 in 12% of DMGs and revealing a more central role for MYC in these cancers than previously known. Applying de novo SV signature discovery, we identified five signatures including three (SVsig1-3) involving primarily simple SVs, and two (SVsig4-5) involving complex, clustered SVs. These SV signatures associated with genetic variants that differed from what was observed for SV signatures in other cancers, suggesting different links to underlying biology. Tumors with simple SV signatures were TP53 wild-type but were enriched with alterations in TP53 pathway members PPM1D and MDM4. Complex signatures were associated with direct aberrations in TP53, CDKN2A, and RB1 early in tumor evolution, and with extrachromosomal amplicons that likely occurred later. All pHGGs exhibited at least one simple SV signature but complex SV signatures were primarily restricted to subsets of H3.3K27M DMGs and hemispheric pHGGs. Importantly, DMGs with the complex SV signatures SVsig4-5 were associated with shorter overall survival independent of histone type and TP53 status. These data inform the role and impact of SVs in gliomagenesis and mechanisms that shape them. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1093/neuonc/noac079.275 |
| الإتاحة: | https://doi.org/10.1093/neuonc/noac079.275Test https://academic.oup.com/neuro-oncology/article-pdf/24/Supplement_1/i75/43945374/noac079.275.pdfTest |
| حقوق: | https://creativecommons.org/licenses/by-nc/4.0Test/ |
| رقم الانضمام: | edsbas.38FD629D |
| قاعدة البيانات: | BASE |
| DOI: | 10.1093/neuonc/noac079.275 |
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